Restoring function in exhausted CD8 T cells during chronic viral infection.

Barry Rouse

Barry Rouse

Barry Rouse

+ -1 Evaluators

Resurrecting moribund memory T cells is the concept of this noteworthy paper from Barber and collaborators. It was previously reported that CD8+ memory T cells generated by persistent viruses, especially if T cell help is in short supply, fail to function and die in the absence of antigen {1}. As is now observed, a critical event occurring in such exhausted T cells is the upregulation of PD-1, a receptor for some members of the B7 family. More interestingly, they show that the exhausted cells can be rejuvenated by blocking the binding of PD-1 to its receptor and that mice receiving such treatment are better able to manage their persistent infection. Should this approach be applicable to the clinic, then some chronic infections such as those caused by hepatitis C and perhaps even HIV could be controlled.

Etienne Joly

Etienne Joly

Etienne Joly

+ -1 Evaluators

In this paper, the authors investigate the functions of cytotoxic T lymphocytes (CTLs) from mice with a persistent viral infection (lymphocytic choriomeningitis virus, LCMV) and demonstrate that blocking the cell surface molecule PD-1 (programmed death-1) has the effect of reviving 'exhausted' anti-LCMV CTLs. The PD1 surface molecule has previously been reported to signal negatively in lymphocytes when it binds to its ligand PD-L1/B7-H1. In the present study, the authors found that administration of anti-PD-1 antibodies restores the ability of exhausted CTLs to proliferate, secrete cytokines, kill virally infected cells and control viral load. CTL exhaustion probably plays an important role in the establishment of persistent viral infections. These observations could have important relevance to the development of therapeutic vaccines against persistent viruses, particularly against HIV.

Christian Engwerda

Christian Engwerda

Christian Engwerda

+ -1 Evaluators

This paper compares the gene expression profiles of CD8 T cells from mice either acutely or chronically infected with two strains of lymphocytic choriomeningitis virus (LCMV), that are genetically identical except for 2 amino acids, and demonstrates that CD8 T cells from chronically infected mice, but not acutely infected mice, express high levels of PD-1, a negative costimulatory molecule that binds to PD-L1 (also known as B7-H1). Furthermore, blockade of the PD-1/PD-L1 interaction with an anti-PD-L1 antibody restores the ability of virus specific CD8 T cells to proliferate, produce cytokine, kill infected cells and reduce viral load. This work has identified a potentially effective means of treating chronic viral infections.

Nicholas Restifo

Nicholas Restifo

Nicholas Restifo

+ -1 Evaluators

The tumor immunotherapist in me found this article to be incredibly exciting. Like workers in the field of chronic infectious diseases, tumor immunologists are faced with attempting to trigger activation in T cells that have lost functionality as a result of chronic antigen exposure. Ahmed and his team convincingly show that it may be possible in one model (lymphocytic choriomeningitis virus, LCMV) to reverse T cell "exhaustion" by blocking negative regulatory signals sent via PD-1. These findings vividly illustrate the kind of maneuver that may enable successful vaccines and immunotherapies for cancer and chronic infectious disease where "exhaustion" seems an apt metaphor for T cells that are plentiful but ineffective.

Allan Zajac

Allan Zajac

Allan Zajac

+ -1 Evaluators

This seminal study reports the use of programmed death (PD)-ligand 1/PD-1 blockade therapy to enhance the numbers and functional quality of virus-specific CD8 T cells and promote the clearance of chronic lymphocytic choriomeningitis virus (LCMV) infection. This report furthers our understanding of the phenomena of T cell exhaustion and describes a novel approach for boosting otherwise ineffective responses.

Linda Bradley

Linda Bradley

Linda Bradley

+ -1 Evaluators

Chronic infections represent a key challenge for development of effective vaccines. The previously unknown possibility that functionally impaired T cells that are found in persisting infections have the capacity to be restored to immunologic competence is revealed in this study. Blocking the molecule programmed death 1 (PD-1) re-establishes antigen-induced expansion of CD8 T cells as well as their development of effector functions, including cytokine secretion, cytotoxicity, and viral clearance in a murine model with LCMV infection. The results suggest that _targeting PD-1 receptor-ligand interactions may be an effective clinical approach to aid in the treatment of chronic infections.

Jonathan Green

Jonathan Green

Jonathan Green

+ -1 Evaluators

Excellent paper that defines the mechanism of immune exhaustion in chronic lymphocytic choriomeningitis virus (LCMV) infection. This paper directly attributes the non-functional status of CD8 T cells in chronic LCMV to signaling through PDL1:PD1 interactions.

Lieping Chen

Lieping Chen

Lieping Chen

+ -1 Evaluators

This is an interesting study showing that blockade of interaction between B7-H1, a molecule of the B7 family, and its inhibitory receptor PD-1 on T cells by a neutralizing monoclonal antibody could block T cell exhaustion due to chronic lymphocytic choriomeningitis virus (LCMV) infection in a mouse model. These findings may have implications in the treatment of virally induced hepatitis.

Michel Goldman

Michel Goldman

Michel Goldman

+ -1 Evaluators

This paper demonstrates that CD8 T lymphocytes which lost their cytotoxic functions during chronic viral infection can recover efficient activities after blockade of the inhibitory pathway involving the programmed death 1 (PD-1) molecule expressed at their membrane. These findings suggest that the PD-1/PD-1-ligand pathway represents a key _target for the development of novel immunointervention strategies to fight chronic infections caused by HIV or hepatitis C virus.

Luis J Montaner

Luis J Montaner

Luis J Montaner

+ -1 Evaluators

The mechanisms for an impaired CD8 T-cell response in the face of continued activation of T-cell responses during a chronic viral infection remains an active area of investigation. While multiple hypotheses with regard to clonal exhaustion, impaired T-cell help, and T-cell epitope escape have been raised (to name a few), the present manuscript identifies a molecule that is expressed in CD8 T-cells and can act to actively inhibit the ability of the CD8 T-cell to respond. The authors propose that this may be a natural negative switch to an immune response which, in the context of a chronic unresolved viral infection, may turn into a primary mechanism of immunodeficiency. Most interestingly, the authors show an increase in CD8 function following blockage of this molecule in the absence of CD4 T cell help to suggest this mechanism may be independent of other factors in affecting CD8 function. Future work will determine if these observations may open the way to novel strategies to monitor, inhibit or stimulate CD8 responses.

Arthur Hurwitz

Arthur Hurwitz

Arthur Hurwitz

+ -1 Evaluators

When your T cells are dead-tired, who you gonna call? PD-L1 Blockade. Clonal exhaustion is a means of generating T cell tolerance to viral, self, and tumor antigens. Barber et al. demonstrate that blocking programmed death-ligand 1 (PD-L1):PD-1 interactions, unlike CTLA-4 blockade, can prevent and reverse exhaustion, even in the absence of CD4 help. As we gain greater understanding of PD-1:PD-L1,L2 interactions, PD-1 may be exploited for therapy of a variety of viral diseases and cancer.

Sibylle Schneider-Schaulies

Sibylle Schneider-Schaulies

Sibylle Schneider-Schaulies

+ -1 Evaluators

Using a classic model of viral persistence in its natural host, this study elegantly documents mechanisms underlying exhaustion of effector T cells and moreover, how proliferation and function of these 'dormant cells' can be restored. Since exhaustion of T cells may be central to the pathogenesis of clinically highly important chronic infections in humans, such as AIDS and chronic hepatitis, the findings obtained in this experimental system are likely to contribute essentially to the development of therapeutic strategies in humans as well.

Grant McFadden

Grant McFadden

Grant McFadden

+ -1 Evaluators

This is a significant contribution because it provides a new strategy for re-awakening CD8-positive T-cells that have lapsed into quiescence during a chronic virus infection. In this paper, the authors show that in mice chronically infected with lymphocytic choriomeningitis virus, the reactive T-cells against the virus were inactive until they were awakened by blockade of a receptor known as PD-1. Thus, manipulation of PD-1 or its natural ligands may provide a new strategy to re-invigorate a cellular immune response to a variety of pathogens in which the T-cell response has become dormant over time.

Matthias von Herrath

Matthias von Herrath

Matthias von Herrath

+ -1 Evaluators

I found this article of high interest because it illustrates how a persistent viral infection could be resolved by interfering with the programmed death 1 (PD1)/PD1-L pathway. The ability to resolve a persistent viral infection without enhancing immunopathology is a crucial new step in immunotherapy. These findings should be the first step in pointing us towards a new direction in intervening in viral persistence.

Pierre Coulie

Pierre Coulie

Pierre Coulie

+ -1 Evaluators

This very clear article reports the effect of an antibody that prevents the interaction of the T-cell inhibitory receptor PD-1 with its ligand, which could be very important for the development of anti-HIV or anti-tumor vaccines. The authors administered anti-PD-1 antibodies to mice, which enhanced T-cell responses considerably. They described a potential mechanism by which anti-PD-1 antibodies may restore activity of functionally impaired anti-virus CD8 T-cells during a chronic viral infection.

Scott Gray-Owen

Scott Gray-Owen

Scott Gray-Owen

+ -1 Evaluators

A fine balance between activating and inhibitory signals undoubtedly controls whether cells respond to any stimuli. This remarkable study suggests that continual signaling through an expressed co-inhibitory receptor, PD-1, can also maintain a cell in an unresponsive state. Simple removal of this signal allows such 'exhausted' CD8+ T cells to rejoin the battle against a chronic viral infection, resulting in increased clearance of the pathogen. However, just as importantly, mice lacking PD-1 ligand died from an overwhelming immune response to a viral strain that is not otherwise lethal. This work provides support for the awesome potential of harnessing the immune response to clear chronic pathogens and cancer, while also demonstrating how the immune system's ability to precisely control a response is a life or death responsibility.